magic fluorine chemistry for medicinal chemistry applications · 2012-09-06 · organofluorine...
TRANSCRIPT
Magic Fluorine Chemistry for Medicinal Chemistry Applications
Wei Zhang
University of Massachusetts Boston
NEACT 72nd Annual Summer ConferenceSt. Joseph’s College, Maine. August 1-4, 2011
Presentation Outline
• Fluorine facts
• History background
• Commercial applications
• Medicinal chemistry
- Organofluorine Chemistry
- Fluorous Chemistry
Atomic Number: 9Relative Atomic Mass: 18.998Group # VIIA (halogens)Quantum # I = ½ (19F NMR, MRI) 19F Abundance ≈ 100%
Fluorine Facts
Bond Average
Bond Strength (KJ/Mol)
Average Bond Length
(Å)
C-F 485 1.39
C-C 356 1.53
C-O 336 1.43
C-H 416 1.09
Element Van der Waals radii (Å)
Electronegativity (Pauling)
F 1.47 3.98
O 1.52 3.44
N 1.55 3.04
C 1.70 2.55
H 1.20 2.2
• Hydrogen fluoride (HF) was first reported by Scheele in 1771.
• In 1836 Dumas and Pelig reported the synthesis oforganofluorine compound fluoromethane.
• In 1886 Henri Moissan isolated molecular elemental fluorinegas (F2).
• Belgian chemist Swarts’ work between 1890 and 1938 onsimple aliphatic fluorocarbons is widely considered asestablishing the foundations of organofluorine chemistry.
• The chemistry of perfluorinated (fully fluorinated) organiccompounds began in 1926 when Lebeau and Damienssynthesized carbon tetrafluoride (CF4).
History of Fluorine
• In the 1930’s, Midgley and Henne extended Swarts’exchange reaction methods for chlorofluorocarbon (CFC).
• In WWII, Uranium hexafluoride (UF6) used in the U-235enrichment process for making atomic bombs.
• DuPont and GM were the pioneers of the application ofCFCs as refrigerants. Later CFC’s found diverseapplications as fire extinguishers, blowing/cleaning agents.
• Most recent applications are related to organofluorineproducts (containing F-C bonds).
History of Fluorine (continue)
• Only 13 known nature organofluorine compounds (2003)
• Most of these are tropical plant metabolites makes the plantsacutely toxic (traces of fluoroacetic acid found in the plant,gifblaar (Dichapetalum cymosum) in the South African veldtare believed to be responsible for numerous cattle deathsfrom errant grazing)
• Mother nature (the best chemist) does not seem to specializein fluorine chemistry
• F is the 13th most abundant element in theearth’s crust (Fluorspar, CaF2)
Nature Occurring Organofluorine Compounds
Possible reasons:
• Nature needs fluoride ion (F-) to be a nucleophile in aqueous
solution. But fluoride ion is generally only available in insoluble
mineral forms, and even the soluble ones provide a fluoride ion
so well-solvated it is a poor nucleophile, which makes ionic or
radical fluorination mechanisms unlikely.
• First fluorinase enzyme was only found until 2002 (Nature, 416,
279).
Why?
Material Chemistry - Fluoropolymers
TeflonNon-stick cookware
Biocompatible materials for implants and cosmetic surgeries
waterproof
breathable fabricsStainmaster carpet
Polytetrafluoroethylene (PTFE)
Liquid crystalsSurfactant
Ionic liquids
Fluoromaterails and Solvents
Organic layer
Aqueous layer
Fluorous layer
C6F14
Fluorinated solvents
Medical Application - 19F MRI
Nuclear Magnetic Resonance Imaging
Perfluorodecaline
Bio Application - Artificial Blood
good O2 and CO2
dissolving power, nontoxic
and highly stabile
Scuba Mouse
Medical Application - Drugs
~1/5 Drugs on the market containing fluorine
Fluorine in Medicinal Chemistry and Chemical BiologyIwao Ojima (Editor), Wiley-Blackwell, 2009
Biologically:
- electronegativity effect of neighbouring functionalities
- strength C-F bonds resistant to metabolic processes
- increases lipid solubility (bioavailability)
- synthesis of isosteric analogues of drugs
- useful for studying biochemical processes
Chemically:
- small size
- lipophilic
- high electronegativity
- low reactivity
Features of Organfluorine Molecules
Publisher: Elsevier
Editor: W. Dolbier
IF (2010): 1.719
Fluorine Chemistry
ACS Division of Fluorine Chemistry
Four Int. Conference Series: 1) Winter Fluorine Conf.; 2) Int. Symp. Fluorine Chemistry; 3) European Symp. Fluorine Chemistry; 4) ACS Nat. Meeting
To Annette and Alexander:
“The fury of the chemical world is the element fluorine. Itexists peacefully in the com- pany with calcium in fluorsparand also in a few other compounds; but when isolated, as itrecently has been, it is a rabid gas that nothing can resist.”
Scientific American, April 1888
“Fluorine leaves nobody indifferent; it inflames emotions bethat affections or aversions. As a substituent, it is rarelyboring, always good for a surprise, but often completelyunpredictable.”
M. Schlosser, Angew. Chem. Int. Ed. 1998, 37, 1496–1513.
Fluorous Chemistry
A New Field of Fluorine ChemistryStarted from 1994
Biphasic System - Temperature-dependent miscibility
Triphasic Cocktail - Organic/aqueous/fluorous
Perfluorinated (fluorous) molecules are lipophobicand hydrophobic
Fluorous Biphasic Catalysis
Two phases One phase Two phases
“Heavy fluorous” - high fluorine content (60%)
• Use phase tagging technique
for easy separation
• Render molecules to fluorous byattaching to fluorocarbon tag
• Fluorous molecules separatedfrom non-fluorous moleculesbase on fluorophilicity
• Fluorous tag are highly selectivefor separation, but low reactive
Fluorous separation
Concept of Fluorous Chemistry
Handbook of Fluorous Chemistry
Gladysz, J. A.; Curran, D. P.; Horvath, I. T. Eds. Wiley-VCH, 2004.
Non-fluorous Fluorous
Fluorous Chemistry - Challenges
1) Persistent nature of perfluorinated compounds
2) Potential toxicities of some perfluorinated compounds
3) Cost of F-solvents for BP reaction & LL extraction
4) High fluorine content only good for catalysis
“Light Fluorous Synthesis” - A Possible Solution
1) Haircut of heavy fluorous ponytails (lower the cost)
2) Fluorous solid-phase extraction (F-SPE) for seperation
3) No F-solvents for reactions and separations
4) Better solubility/reactivity in common organic solvents
Zhang, W. Green Chem. 2009, 11, 911-920.
Heavy and Light Fluorous PMB Linkers
F-SPEF-LLE
Don’t need fluorous solvent
Fluorous Separation Techniques
Need fluorous solvent
Zhang, W. Tetrahedron 2003, 59, 4475.
“Heavy fluorous” “Light fluorous”
Fluorous Silica Gel
F-SPE silica gel (~100 mm)
Selective retention of light fluorous molecules
Zhang, W.; Curran, D. P. Tetrahedron 2006, 62, 11835.
Fluorous SPE (F-SPE)
IT
F
FF
O O
O
T
F FF
O
O
O
T
F
F
F
S ilica
O
S i(Me) 2
R f
I I
organic fraction
fluorous fraction
fluoroussilica gel
Fluorophobic Solvent (MeOH-H2O)
Fluorophilic Solvent (MeOH)
Curran, D. P. Synlett 2001, 1488
- Use MeOH-H2O as elution solvent
- Cartridge can be reused after wash with acetone or THF
Zhang, W.; Curran, D. P. Tetrahedron 2006, 62, 11837.
O
O
NH
F
C7F
15
O
O
NH
NH
C4H
9
C4H
9
Solvent Blue
F-Orange
Left tube: beginning of fluorophobic wash (80:20 MeOH:H2O);
Center tube: end of fluorophobic wash;
Right tube: end of fluorophilic wash (100% MeOH)
Fluorous SPE
Light Fluorous Compounds
SHN
O
NO
O
O
P
Ph
Ph
Sn
Rf
Rf
H
O
O
ON
NC
NC
N
OO
O
O
O
Ph
Ph
OH
Si
Rf
Rf
H
NN
N
OH
NN
N
O
Cl
Cl
OH
S
S O
O
O
OCl
S O
OF
O
NH
N
O
Ph
PPh2
PdCl2
NCo
OO
NH H
Rf
t-Bu Bu
N
N
O
O
NN
O O RfN
+
Cl
NN
NO
O
F-TagC8F17(CH2)n
Reagents
Linkers
Catalysts
Scavengers
2
t
(AcO)2I
C6F13(CH2)n
Fluorous Synthesis
I. Fluorous Molecules
- Catalysts
- Reagents
- Scavengers
- Linkers (Tags)
II. Fluorous Separation Tools- Liquid-liquid extraction
- Solid-phase extraction
- Chromatography
Zhang, W. Tetrahedron 2003, 59, 4475.
Fluorous Techniques for Medichem Applications
1) Solution-phase reaction kinetics
2) Easy adaptation of literature procedures
3) Monitoring reactions by TLC, HPLC, LC-MS, or NMR
4) Chromatography-free separations (F-SPE)
5) Integrating with microwave, MCR, DOS, SPS…
6) Recovery of fluorous materials
Medichem
Medicinal Chemistry in Drug Discovery
It takes 12 to 15 years and costs $0.8 to 2 billions to develop a new drug
• Medichem program requires large numbers of compounds(libraries) for screening
• Compound purification is the bottle-neck in library synthesis
• Combinatorial Chemistry and high-throughput synthesis
++
MW Reactor LC-MS F-SPE
Integrated Fluorous Technologyfor parallel and HTP Synthesis
Fast reaction Quick analysis Easy separation
Zhang, W. Topics Curr. Chem. 2006, 266,145.
Fluorous Tagging Strategies
+de-tag
F-SPE
F F
� Tagging reactants for parallel and mixture syntheses
� Tagging reagents/catalysts/scavengers
Reagent
Derivative
clean product
F-SPE+
F
F
Curran, D. P. Angew. Chem. Int. Ed. Eng. 1998, 37, 1175.
Zhang, W. Tetrahedron 2003, 59, 4475.
O
CHO
OMe
OMeC8F
17
R
NH
O
OMe
F-Bn
NH2
CO2H
PhNOLi
Me
R
RN
RO
F-Bn
O
NH2
OMe
R
NH
N
R
O
O
F-Bn
R
NH2 . HCl
O
OMe
CO2Cl
NO2
R
N
N
R
OF-Bn
OO
O2N
N
R
O
NN
O
H
RN
R
O
NN
O
F-Bn
O
OMe
OMeC8F17 R
DIPEA, AcOH DCM, 25 oC
EDCI, NMP
THFreflux, 1 h
NaBH(OAc)3
F-SPE
64-95%
43-69% (2 steps)
F-SPE
1
1
2
2
1
2 1
t-BuN=P(NMe2)3
Zn, AcOH
sonication
90:5:5TFA-H2O-DMS
F-SPE HPLC
72-90%
µw 120 oC,10 min
F-SPE
21-73%
63-100%
2 1 2 1
1
F-Bn = 2
9 analogs
Synthesis of Sclerotigenin Analogs
Only one step needs LC purification
Lu, Y.; Nagashima, T.; Miriyala, B.; Conde, J.; Zhang, W. J. Comb. Chem. 2010, 12, 125.
144
Microwave-Assisted Fluorous Multicomponent Reactions
Zhang, W. Comb. Chem. High Throughput Screening 2007,10, 219.
F
excess non-fluorouscomponents
µwF
F-SPE F-SPE
F-intermediate fishedout by F-SPE
clean product
µwF
excess non-fluorouscomponents
µwF
F-SPE F-SPE
F-intermediate fishedout by F-SPE
clean product
µw
Atom economy, fast reaction, simple separation
Synthesis of Benzodiazepinediones
Liu, A.; Zhou, H.; Su, G.; Zhang, W.; Yan, B. J. Comb. Chem. 2009, 11, 1083.
N
HN
O
O
R3
HN
O
R4
C8F17O2SOR2
R1
CHO
C8F17O2SO
R2
NHBoc
OH
O
OR
O
H2NR1
R3
CN R4
UgiN
O
R3
NH
OR4
R2
BocHN
R1
OSO2C8F17
+
CO2R
N
HN
O
O
R3
HN
O
R4
R2
R1Suzuki
65 analogs
R5PhB(OH)2deBoc
R5
AcCl, MeOH, 35 oC
F-SPE
KOH, MeOH, rtF-SPE
Pd(pddf)Cl2
K2CO3
acetone/toluene/H2O
(4:4:1), w. 150oC
Diversity Oriented Synthesis (DOS)
R4
NR3
O
O
H
H
R1
N
N
O
O
R2
NR3
O
ONH
H
H
R1 O
O (CH2)3Rf
R2 R2
NR3
O
O
H
H
R1
N
NHO
O
R1
NH2
O
O (CH2)3Rf NR3
O
O
CHO
R2
R4
NR3
O
O
H
H
R1
N
N
O R4
O
R2
+ +
[3+2]
480 analogs 60 analogs
Zhang, W.; Lu, Y.; Chen, C. H.-T.; Curran, D. P.; Geib, S. Eur. J. Org. Chem. 2006, 2055.
90 analogs
Benzodiazepine-Fused System
Zhang, W.; Lu, Y.; Chen, Chen, C. H.-T. J. Comb. Chem. 2006, 8, 687.
Hydantoin-fused Hexahydrochromeno[4,3-b]pyrroles
One-pot synthesisSingle fluorous linker8 Diastereomers
Fluorous Diastereomeric Mixture Synthesis (FDMS)
Lu, Y.; Geib, S. J.; Damodaran, K.; Sui, B.; Zhang, Z.; Curran, D. P.; Zhang, W. Chem.
Commun. 2010, 46, 7578-7580.
O
CO2Et
NN
O
O
H
H
BrOMe
cis-anti-trans
1a
cis-syn-cis
O
CO2Et
NN
O
O
H
H
BrOMe
1a'
trans-anti-cis1b
O
CO2Et
NN
O
O
H
H
BrOMe
trans-syn-trans
1b'
O
CO2Et
NN
O
O
H
H
BrOMe
(not isolated)
O
CO2Et
NN
O
O
H
H
BrOMe
1c
cis-anti-cis
O
CO2Et
NN
O
O
H
H
BrOMe
1c'
cis-syn-trans(not isolated)
trans-anti-trans
O
CO2Et
NN
O
O
H
H
BrOMe
1d
trans-syn-cis
CO2Et
NN
O
O
H
H
BrOMe
1d'
6 Diastereomers Isolated from a Mixture of 8
3
1
2
A B A B
Normal TLC2:1 hex-EtOAc
Fluorous TLC4:1 MeOH-H2O
Sample A contains 1 and 3Sample B contains 2 and 3
TLC of fluorous and non-fluorous mixtures
F-SPE
Organocatalysis
Pros- Metal free & environmental friendly
- Novel catalysis mechanism
- Mimic natural chemo- and biocatalysis
- Good structure amendablilty
Cons - Low efficiency & high catalyst loading (5-30%)
- Recycling is necessary
PS-organocatalysts are recycable, but may have
low activity because of the heterogeneous natural
F-organocatalysis is homogeneous and recycable
Zhang, W.; C. Cai, Chem. Commun. 2008, 5686.
F-Imidazolidinone (MacMillan) Catalyst
Chu, Q.; Zhang, W.; Curran, D. P. Tetrahedron Lett. 2006, 47, 9287.
NH
N
O
Ph
NH
N
O
Ph
C8F
17
H
O CHOCHO
organic
+ +
endo (major) exo
cat. (10 mol %)
MeCN-H2O, 25 oC, 40 h
82% 90.3 : 9.7 88.4 65%a 74%
catalyst yield endo:exo ee% cat purity of (endo) recovery recovered cat
a by acid-base extraction. b by F-SPE
catalyst
fluorous
Diels-Alder
organic
fluorous 86% 93.4 : 6.6 93.4 84%b 99%
Comparison of Organic and Fluorous
analyzed by chiral GC
93.4% eeCHO88.4% ee
CHO
NH
N
O
Ph
exo
endo
Organic Fluorous
catalyst
NH
N
O
Ph
C8F
17
“Organofluorine” & “Fluorous” Chemistries
Organofluorine Chemistry
- Reaction-oriented chemistry
(fluoropolymers and fluorinated drugs)
- Associate with transformation of C-F bonds
- Fluorine atom(s) in the product
Fluorous Chemistry
- Purification/labeling-based chemistry
- Use highly fluorinated group to tag substrates
- No C-F bond formation is necessary
- Products do not need to have fluorine
Zhang, W. QSAR Comb. Science 2006, 25, 679.
Broad Applications
Zhang, W.; Cai, C. Chem. Commun. 2008, 5686.
Solution-Phase Reaction
Fluorous Separation
Microwave Reaction
Fluorous Chemistry
Mixture Synthesis
Nanotechnology
Biphasic Catalysis
Diversity-Oriented Synthesis
Biomolecule Purification1994
1997
2006
2004
2001
2001
Triphasic Reaction
2001
Microreactor
Microarray
2006
2003
Parallel Synthesis
1997
SciFinder search on “Fluorous”
Over 2000 Publications
Key Contributors
- Dennis P. Curran (246)
- John A. Gladysz (152)
- Wei Zhang (118)
- Istvan T. Horvath (83)
First Fluorous Book (2004)
Two Special Issues in 2002 & 2006
Tetrahedron Symposium-In-Print“Fluorous Chemistry”
Guest Editors: J. A. Gladysz and D. P. Curran
Tetrahedron 2002, 58, 3823-4131
Guest Editor: W. Zhang
QSAR Comb. Science 2006, 25 (8-9), 679-768
“Fluorous Synthesis”
Fluorous Conferences
1st Int. Symp. on Fluorous Technologies
Bordeaux, France, July 3-6 2005
Co-Chairmen: J.-M. Vincent and R. H. Fish
ACS Symp. “Recent Advances in Fluorous
Chemistry”
ACS National Meeting, Washington D.C
August 27-31, 2005Chairman: D. P. Curran
2st Int. Symp. on Fluorous Technologies
Yokohoma, Japan, July 29-August 1, 2007
Chairman: Junzo Otera
3st Int. Symp. on Fluorous Technologies
Jackson Hole, USA, Aug. 23-28, 2009
Chairman: D. P. Curran
Zhang, W. Green Chem. 2009, 11, 911.
Fluorous and Green Chemistry
Dr. Paul Anastas
BS: 1984 UMB, Ph.D: 1988 Brandies
Yale University, EPA Assistant Administrator
Dr. John C. Warner
BS:1984 UMB, Ph.D: 1988 Princeton
Warner Babcock Institute of Green Chemistry Institute
President and Chief Technology Officer
Dr. Berkeley W. Cue
BS:1969 UMB, Ph.D: 1973 Univ. Alabama
VP Pfizer Global R&D (retired)
BWC Pharma Consulting, LLC
Chairman, ACS Green Chemistry Institute Governing Board
UMB Alumni in Green Chemistry
1st Ph.D. in Green Chemistry
3rd Int. Symp. of Green Chemistry at UMB
Sept. 30 to Oct. 1, 2010
Current Group Members
UMass Boston Campus
John Hancock Downtown Boston Logan Airport
JFK Library